Frameshift mutation of Timm8a1 gene in mouse leads to an abnormal mitochondrial structure in the brain, correlating with hearing and memory impairment.
J Med Genet
; 58(9): 619-627, 2021 09.
Article
en En
| MEDLINE
| ID: mdl-32820032
ABSTRACT
BACKGROUND:
Deafness-dystonia-optic neuronopathy (DDON) syndrome is a progressive X-linked recessive disorder characterised by deafness, dystonia, ataxia and reduced visual acuity. The causative gene deafness/dystonia protein 1 (DDP1)/translocase of the inner membrane 8A (TIMM8A) encodes a mitochondrial intermembrane space chaperon. The molecular mechanism of DDON remains unclear, and detailed information on animal models has not been reported yet. METHODS ANDRESULTS:
We characterized a family with DDON syndrome, in which the affected members carried a novel hemizygous variation in the DDP1 gene (NM_004085.3, c.82C>T, p.Q28X). We then generated a mouse line with the hemizygous mutation (p.I23fs49X) in the Timm8a1 gene using the clustered regularly interspaced short palindromic repeats /Cas9 technology. The deficient DDP1 protein was confirmed by western blot assay. Electron microscopic analysis of brain samples from the mutant mice indicated abnormal mitochondrial structure in several brain areas. However, Timm8a1I23fs49X/y mutation did not affect the import of mitochondria inner member protein Tim23 and outer member protein Tom40 as well as the biogenesis of the proteins in the mitochondrial oxidative phosphorylation system and the manganese superoxide dismutase (MnSOD / SOD-2). The male mice with Timm8a1I23fs49X/y mutant exhibited less weight gain, hearing impairment and cognitive deficit.CONCLUSION:
Our study suggests that frameshift mutation of the Timm8a1 gene in mice leads to an abnormal mitochondrial structure in the brain, correlating with hearing and memory impairment. Taken together, we have successfully generated a mouse model bearing loss-of-function mutation in Timm8a1.Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Encéfalo
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Mutación del Sistema de Lectura
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Proteínas del Complejo de Importación de Proteínas Precursoras Mitocondriales
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Trastornos de la Audición
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Trastornos de la Memoria
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Mitocondrias
Tipo de estudio:
Diagnostic_studies
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Prognostic_studies
Límite:
Adult
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Animals
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Humans
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Male
Idioma:
En
Revista:
J Med Genet
Año:
2021
Tipo del documento:
Article
País de afiliación:
China